Project Summary/Abstract Resident macrophages are often the first cells to detect bacterial contamination of a tissue, and use inflammatory caspases such as caspases-1 and -11 to distinguish virulent from avirulent bacteria. When activated by sensors that detect pathological bacterial activity, caspase-1 processes pro-IL-1? and pro-IL- 18 to their mature and secreted forms to recruit additional immune cells. In addition, caspase-1 also triggers a lytic form of programmed cell death called pyroptosis. In contrast, caspase-11 induces pyroptosis, but cannot process pro-IL-1? or IL-18 alone. Neutrophils are a major cell type recruited to early sites of infection. However, whether neutrophils also express inflammatory caspases in order to detect bacterial virulence remains unclear. Intriguingly, neutrophils express numerous pattern recognition receptors and sensors upstream of caspases, but their function in infection has not been thoroughly studied. Given the importance of inflammasomes in macrophages, and the importance of neutrophils in sterilizing infection, it is likely that neutrophils also use inflammasomes to tune their responses to infection. Indeed, we found that neutrophil caspase-11 is activated and clears infected neutrophils with extreme efficiency. Thus, in this grant, we propose to compare and contrast the inflammasome signaling pathways in neutrophils and macrophages, and determine the role of inflammasome in each cellular compartment during defense against intracellular and extracellular infection. Determining the role of inflammasomes in neutrophils may provide new perspectives about the function of neutrophils during infection, as well as insight into potentially novel and innovative therapeutic strategies aimed at preventing cytosolic infection in neutrophils.